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Repurposing Atovaquone as a Therapeutic against Acute Myeloid Leukemia (AML): Combination with Conventional
Alexandra McLean Stevens1, Eric S Schafer1, Minhua Li2
1Department of Pediatric Hematology/Oncology, Texas Children's Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA.
Insights
Atovaquone (AQ) combined with chemotherapy is a feasible and safe treatment for pediatric acute myeloid leukemia (AML). This approach shows anti-leukemic effects and may improve survival in young patients.
Area of Science:
- Oncology
- Pharmacology
- Pediatric Medicine
Background:
- Pediatric acute myeloid leukemia (AML) survival rates remain low despite intensive myelosuppressive therapies.
- Atovaquone (AQ), a medication for Pneumocystis jiroveci pneumonia (PJP), demonstrates anti-leukemic properties by suppressing oxidative phosphorylation (OXPHOS) and reducing AML burden in preclinical models.
- Challenges with AQ palatability and formulation have hindered its use in pediatric AML.
Purpose of the Study:
- To evaluate the feasibility, safety, and preliminary efficacy of combining atovaquone (AQ) with standard chemotherapy in pediatric patients with de novo AML during Induction 1.
- To assess AQ pharmacokinetics (PK), compliance, and adverse events (AEs) in this patient population.
- To explore AQ's anti-leukemic mechanisms, including apoptosis induction and OXPHOS suppression.
Main Methods:
- A prospective study enrolled pediatric patients with de novo AML receiving standard chemotherapy combined with daily AQ at PJP dosing.
- Data collected included AQ compliance, AEs, ease of administration scores, and blood/marrow PK.
- Correlative studies analyzed AQ's effects on apoptosis and OXPHOS in patient samples, alongside efficacy in patient-derived xenograft (PDX) models.
Main Results:
- Twenty-six patients were enrolled; 24 were evaluable. A significant proportion (58% by day 11, 79% by end of Induction) achieved anti-leukemic plasma concentrations (>10 µM).
- Mean ease of administration score was 3.8, indicating moderate ease of use.
- Correlative studies confirmed AQ-induced apoptosis, OXPHOS suppression, and prolonged survival in PDX models, while only 29% achieved PJP prophylaxis concentrations (>40 µM).
Conclusions:
- Combining AQ with chemotherapy for pediatric AML is feasible and safe during Induction 1.
- AQ exhibits single-agent anti-leukemic effects in preclinical models and induces apoptosis and OXPHOS suppression in patient samples.
- Further dose optimization may be needed to achieve adequate concentrations for PJP prophylaxis alongside anti-leukemic effects.
Abstract:
Survival of pediatric AML remains poor despite maximized myelosuppressive therapy. The pneumocystis jiroveci pneumonia (PJP)-treating medication atovaquone (AQ) suppresses oxidative phosphorylation (OXPHOS) and reduces AML burden in patient-derived xenograft (PDX) mouse models, making it an ideal concomitant AML therapy. Poor palatability and limited product formulations have historically limited routine use of AQ in pediatric AML patients. Patients with de novo AML were enrolled at two hospitals. Daily AQ at established PJP dosing was combined with standard AML therapy, based on the Medical Research Council backbone. AQ compliance, adverse events (AEs), ease of administration score (scale: 1 (very difficult)-5 (very easy)) and blood/marrow pharmacokinetics (PK) were collected during Induction 1. Correlative studies assessed AQ-induced apoptosis and effects on OXPHOS. PDX models were treated with AQ. A total of 26 patients enrolled (ages 7.2 months-19.7 years, median 12 years); 24 were evaluable. A total of 14 (58%) and 19 (79%) evaluable patients achieved plasma concentrations above the known anti-leukemia concentration (>10 µM) by day 11 and at the end of Induction, respectively. Seven (29%) patients achieved adequate concentrations for PJP prophylaxis (>40 µM). Mean ease of administration score was 3.8. Correlative studies with AQ in patient samples demonstrated robust apoptosis, OXPHOS suppression, and prolonged survival in PDX models. Combining AQ with chemotherapy for AML appears feasible and safe in pediatric patients during Induction 1 and shows single-agent anti-leukemic effects in PDX models. AQ appears to be an ideal concomitant AML therapeutic but may require intra-patient dose adjustment to achieve concentrations sufficient for PJP prophylaxis.
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